Bone is the most common site of metastasis for patients with breast cancer. Tumor cells migrate to and reside in the protective bone marrow microenvironment niche through adhesive interaction between tumor CXCR4 and stromal CXCL12 (SDF1). CXCL12 is produced by activated osteoblasts, bone marrow and lung stromal cells, and endothelial cells. Nearly 60% of breast cancers express CXCR4 and this is associated with decreased survival. We hypothesized that a Protein Epitope Mimetic (PEM) POL5551, a novel CXCR4 antagonist, will limit the extent of tumor metastasis by disrupting stromal-mediated protection from cytotoxic chemotherapy and in turn may prolong survival.
In vitro, POL5551 had no direct cytotoxic activity and did not reduce proliferation of CXCR4+ MDA-MB-231 or 4T1 osteolytic breast cancer cell lines. However, in an in vitro scratch-wound assay POL5551 inhibited migration of MDA-MB-231 cells. In a Gaussia luciferase (GLuc) complementation model in MDA-MB-231 cells, the interaction of CXCL12 with CXCR4, but not CXCR7, was blocked by low nanomolar concentrations of POL5551. At 20 mg/kg administered from day 10 post inoculation, POL5551 displayed no single agent activity on primary tumor xenografts, and in combination with eribulin there was no synergistic effect on primary tumor xenografts. However, continuation of treatment with POL5551 after surgical tumor removal decreased tumor metastasis and prolonged survival to 58 days compared to control at 45 days and eribulin alone at 51 days. Also, POL5551 showed effects on immune infiltration to the primary tumor. To test the hypothesis that CXCR4 antagonism disrupts the protective bone marrow niche in which tumor cells reside and sensitizes them to cytotoxic chemotherapy, we employed a “framing dosing strategy”. In a second model of metastasis produced by intracardiac injection of MDA-MB-231 cells, POL5551 (20 mg/kg, s.c.) was administered to mice with bone metastases 4 hours before and 4 & 18 hours after eribulin chemotherapy (0.2 mg/kg, i.v.). While bone is the predominant site of metastasis with these cell lines, lung and liver metastasis also occurs. POL5551 in combination with eribulin decreased bone tumor burden more than eribulin alone (reduction in leg bone & liver tumor burden, versus control respectively: eribulin alone 58% & 75%, n.s.; POL5551+eribulin: 89% & 86%, P<0.05; n=4-5 mice per group).
These preclinical data support a synergism of CXCR4 antagonism during chemotherapy for the treatment of metastatic breast cancer. These and additional data support initiation of a Phase I clinical trial to evaluate a related PEM CXCR4 antagonist in combination with eribulin chemotherapy in patients with metastatic breast cancer who have failed at least 2 lines of therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Jingyu Xiang, Michelle A. Hurchla, Kathryn Luker, Garry Douglas, Barbara Romagnoli, Eric Chevalier, Michael Bauer, Johann Zimmermann, Klaus Dembowsky, Gary Luker, Katherine N. Weilbaecher. Combination of a novel CXCR4 antagonist with chemotherapy reduces breast cancer bone metastatic tumor burden. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1114. doi:10.1158/1538-7445.AM2014-1114